This invention relates to the manufacture of intermediates suitable for use in the manufacture of Omeprazole and other medicines and the use thereof to manufacture Omeprazole and other medicines. This invention in its broadest aspects is directed to the manufacture of intermediates useful in the manufacture of medicines such as Omeprazole, Pantoprazole, and Lansoprazole, intermediates suitable for the use to manufacture medicines and the processes for manufacturing the intermediates and for using those intermediates to manufacture medicines.
The reported synthesis of Omeprazole basically involves the coupling of intermediates A and B to form intermediate C which is oxidized to the sulfinyl or sulfoxy compound, Omeprazole. 
(See for example Canadian Letters Patent No. 1,127,158 Hassle)
Hassle used the N-oxide form of intermediate A: 
(See Canadian Letters Patent No. 1,234,118)
The N-Oxide form may be considered necessary to prepare the precursor 4-nitro compound and it is essential for the alkylation/functionalization of the 2-position (X), according to Hassle""s process. Intermediate A (N-Deoxygenated) is then coupled with intermediate B on the route to Omeprazole.
Esteve, on the other hand, described a synthesis that involves coupling the N-oxides of the 4-nitro or the 4-Chloro with intermediate B to form the N-Oxide of intermediate C. Following that, Esteve either substituted at the pyridinyl 4-position with the methoxy and then reduced the N-Oxide or vice-versa. 
R2: xe2x80x94Cl, xe2x80x94NO2, or xe2x80x94OCH3 
(See European Patent No. 484,265)
Torcan, reported a method that offers advantages involving the oxidation and the purification of the final product. Their method comprises oxidizing the amide of Intermediate C to the corresponding amide sulfinyl compound followed by hydrolysis and decarboxylation to form Omeprazole. Torcan did not report processes for the manufacture of the pyridinyl moiety. 
(See U.S. Pat. No. 5,374,730)
Other Oxidation methods used for converting the thioether xe2x80x9cIntermediate Cxe2x80x9d to the sulfinyl are purportedly taught by recent Takeda (CA 1,263,119) and Hassle""s (U.S. Pat. No. 5,386,032) patents.
C. L. Pharma""s U.S. Pat. No. 5,066,810 teaches a process to manufacture 
where X is OH or Cl by catalytic hydrogenation of 3,5-dimethyl-4-methoxy-2-cyanopyridine as depicted below 
in the presence of an inert diluent, the resulting 3,5-dimethyl-4-methoxy-2-aminomethylpyridine as depicted below 
which is then reacted with sodium nitrite in aqueous-acidic solution to give 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine and ultimately reacting the latter with thionyl chloride to give 3,5-dimethyl-4-methoxy-2-chloromethylpyridine.
In European Patent Publication No. 0103553 and in Canadian Letters Patent 1,234,118 and in U.S. Pat. Nos. 4,544,750 and 4,620,008, the following synthetic route for the pyridine part of omeprazole is described: 
More recently, a method for the synthesis of intermediate A was published by a Taiwanese group. This procedure consisted of preparation of the pyrone, pyridone and pyridine derivatives that can be converted to intermediate A. (Heterocycles, 45, 1997, 77).
There are certain disadvantages associated with the current manufacturing processes, largely derived from the N-Oxide intermediates. Nitropyridines and their N-oxides are suspected carcinogens and therefore are unsafe to handle. Also, the above processes employ the nitropyridines and their N-oxides in the early or late stages of the manufacture. In both cases the suspected carcinogens are potential impurities.
While the Taiwanese method does not employ nitropyridines or N-oxides, it suffers from the disadvantage that it employs a large number of steps (approximately 10 steps) and the low availability of the starting material. Both are factors that affect the manufacturing yield and cost.
It is therefore an object of the invention to provide a method of manufacturing intermediates useful in preparing medicines where said intermediates avoid N-oxides that are suspected carcinogens.
It is also another object of the invention to provide methods of manufacturing intermediates useful in preparing medicines where said method employs intermediates that are safe to handle.
It is also another object of the invention to provide methods of manufacturing intermediates useful in preparing medicines wherein the number of steps are minimal in number.
It is also another object of the invention to provide methods of manufacture which incorporate materials that are readily available.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention.
According to one aspect of the invention, there is provided a process of making Compound III (shown hereafter) by reacting a compound of the formula II 
with an organic free radical .R4 (for example prepared in situ) to produce the compound of formula III 
wherein
R1=H or CH3 
R2=H or CH3 
R3=Alkoxy (1-4C), OCH2CF3, Cyano, Hydrogen, Halogen, Acetoxy or Aryloxy, any electron withdrawing group or salts (organic or inorganic) of electron donating groups
R4=Alkyl, Acyl (ketone), Amides (carbamoyl), Alkoxycarbonyl (COOR1, R1=(1-3C)), Aryloxycarbonyl, Carboxylic Acid, Aryloxymethyl (xe2x80x94CH2OAr), Phenoxymethyl, Hydroxymethyl (xe2x80x94CH2OH)
or an obvious chemical equivalent. (The source of R4 may be any suitable compound.)
According to another aspect of the invention, there is provided a process of producing a compound of formula Ixe2x80x2 
using intermediate III. An exemplary process may be by carrying out the following reaction step or steps which are obvious chemical equivalents of the following steps: 
According to another aspect of the invention, there is provided a process of manufacturing Omeprazole by using the intermediate formed by the process above described with the appropriate substituents or an obvious chemical equivalent.
According to another aspect of the invention, there is provided a process of manufacturing Pantoprazole by using the intermediate formed by the process above described with the appropriate substituents or an obvious chemical equivalent.
According to another aspect of the invention, there is provided a process of manufacturing Lansoprazole by using the intermediate formed by the process above described with the appropriate substituents or an obvious chemical equivalent.
According to another aspect of the invention, there is provided a process of forming a compound having the structure 
by reacting a compound having the structure 
R1, R2 and R3 as previously defined, with a radical .alkyl under free radical reaction conditions or an obvious chemical equivalent.
According to another aspect of the invention, there is provided a process of forming a compound having the structure 
by reacting a compound having the structure 
R1, R2 and R3 as previously defined, with a radical .acyl under free radical reaction conditions or obvious chemical equivalent.
According to another aspect of the invention, there is provided a process of forming a compound having the structure 
by reacting a compound having the structure 
R1, R2 and R3 as previously defined, with a radical .amide under free radical reaction conditions or obvious chemical equivalent.
According to another aspect of the invention, there is provided a process of forming a compound having the structure 
by reacting a compound having the structure 
R1, R2 and R3 as previously defined, with a radical .alkoxycarbonyl under free radical reaction conditions or obvious chemical equivalent.
According to another aspect of the invention, there is provided a process of forming a compound having the structure 
by reacting a compound having the structure 
R1, R2 and R3 as previously defined, with a radical .aryloxycarbonyl under free radical reaction conditions or obvious chemical equivalent.
According to another aspect of the invention, there is provided a process of forming a compound having the structure 
by reacting a compound having the structure 
R1, R2 and R3 as previously defined, with a radical .carboxylic acid under free radical reaction conditions or obvious chemical equivalent.
According to another aspect of the invention, there is provided a process of forming a compound having the structure 
by reacting a compound having the structure 
R1, R2 and R3 as previously defined, with a radical .aryloxymethyl (for example, .phenoxymethyl) under free radical reaction conditions or obvious chemical equivalent.
According to another aspect of the invention, there is provided a process of forming a compound having the structure 
reacting a compound having the structure 
R1, R2 and R3 as previously defined, with a radical .hydroxymethyl under free radical reaction conditions or obvious chemical equivalent.
The inventors propose that their approach would be highly suitable for use to make pyridines which are intermediates that could be used to make medicines.
Applicants propose as exemplary of their invention that the following pyridine compound: 
wherein
R1=H or CH3 
R2=H or CH3 
R3=Alkoxy (1-4C), OCH2CF3, Cyano, Hydrogen, Halogen, Acetoxy or Aryloxy, any electron withdrawing group or salts (organic or inorganic) of electron donating groups
R=Alkoxy, Hydroxy, Halogen, Activated ester, Tosylate, Mesylate, Thiol, or Xanthyl
be prepared by the following schemes of reaction (in suitable solvents): 
wherein formula II or III:
R1, R2, R3 are the same as specified in formula I
R4=Alkyl, Acyl (ketone), Amides (carbamoyl), Alkoxycarbonyl (COORxe2x80x2, Rxe2x80x2=(1-3C)), Aryloxycarbonyl, Carboxylic acid, Aryloxymethyl, Hydroxymethyl.
Compound I may then be manufactured using intermediate III.
For the synthesis of an intermediate useful in the manufacture of Omeprazole, the following substituents appear on the intermediate of formula Ixe2x80x2 where R1=R2=CH3; R3=OCH3, R=Cl. An exemplary process of manufacture may be characterized by the steps in Scheme 2A.
a) Functionalization of the 4-Position: (Step 01 in Scheme 2A)
Reacting a compound of the formula II, where R3=H with a halogenating agent, examples include and are not limited to thionyl halide, phosphorous oxyhalide, or phosphorous pentahalide.
This reaction could be carried out in an inert solvent such as toluene, dimethylbenzene, chlorobenzene or could be carried out neat with no solvent, with the halogenating reagent used in excess (2-5 eq.), to be the solvent. The mode of addition of reagents is not important, i.e. pyridine to the halogenating reagent or the halogenating reagent to pyridine. The addition is done dropwise, under nitrogen, at a temperature range of 0-70xc2x0 C. At the end of the reaction the product is obtained as a salt. The free base could be obtained by typical procedures known to a person skilled in the art.
b) Functionalization of the 2-Position: (Step 02 in Scheme 2A)
Reacting the 4-halopyridine with an organic free radical comprised of the R4 groups specified above, preferably the alkoxycarbonyl. Several alkoxycarbonyl radical sources can be used: (see e.g. Tet. Lett. 1973, 645).
For Example;
i. Redox decomposition of oxyhydroperoxides of xcex1-ketoesters (Scheme-2),
ii. Oxidative decarboxylation of semiesters of oxalic acid by peroxydisulfate or lead tetraacetate,
iii. Hydrogen abstraction from alkyl formates.
Method in subparagraph (i) is preferred method because it provides simple conditions and good yields. The pyridine used in this reaction could be in the free base or the salt form. The salt could be prepared prior to the reaction or formed in situ and it is the result of reacting the pyridine with an organic or inorganic acid, preferably sulfuric acid. An inert solvent such as Toluene or Xylene could be added to form a two-phase reaction. If an organic solvent is added, it is preferable in a volume equal to or higher than that of water. In parallel, in another flask the reagent required to functionalize the 2-position on the pyridine moiety, such as the pyruvate (C1-C3) (0.9-3.0 eq.) is cooled to about xe2x88x9210xc2x0 C. and hydrogen peroxide (0.9-3.0 eq.) is added dropwise. This solution and a solution of Iron sulfate heptahydrate (0.9-3.0 eq.) in water are, slowly and simultaneously, added to the pyridine solution which is stirred at 0-5xc2x0 C.
c) Reduction of the R4 Group: (Step 03 in Scheme 2A)
Reacting the group on the 2-position with an appropriate reducing agent to prepare a compound of the formula I, where R corresponds to an OH group. For example, 2-alkoxycarbonyl-4-Halopyridine could be reacted with an appropriate reagent to effect reduction of the ester moiety to an alcohol. Reducing agents such as Diisobutylaluminum Hydride (e.g. Syn 1975, 617) in an appropriate solvent such as toluene, tetrahydrofuran, hexane or a combination of those solvents could be used. Also, sodium bis[2-methoxyethoxy]aluminum hydride (e.g. J. Heterocyclic chem., 1990; 27, 2125; Syn., 1976, 526), borohydrides, such as Sodium or Lithium borohydride, (e.g. J. Org. Chem. 1963, 28, 3261; Tet. 1979, 35, 567;) could be used in a variety of protic solvents such as methanol, ethanol, isopropanol, water, a combination of those solvents and aprotic solvents such as toluene, xylene, ethers or a combination of protic and aprotic solvents. The reduction could be performed by typical procedures known to a person skilled in the art.
d) Nucleophilic Substitution of the Halogen on the 4-Position by an xe2x80x94OCH3 Radical: (Step 04 in Scheme 2A)
Nucleophilic substitution of the halogen on the 4-position by a nucleophile such as a xe2x80x94OCH3 radical can be performed using methoxide salts such as sodium, potassium or copper methoxide (e.g. see Chem and Ind., 1967, 1784). Also, sodium or potassium methoxide could be used in the presence of a copper salt such as cuprous iodide, cuprous bromide or cuprous chloride. The reaction can be carried out in an inert solvent such as dimethylformamide, dimethylacetamide, dimethylsufoxide, diglyme, methanol, or a combination of those solvents. The methoxide salt is used in excess (2-7 eq.) and the reaction temperature could be between 65xc2x0 C. and reflux.
e) Nucleophilic Substitution of the OH Radical by a Halogen
The conversion of the hydroxymethyl moiety on the 2-position to a halomethyl, for example, chloromethyl could be achieved by employing methods known to a person skilled in the art, e.g. using thionyl chloride in an inert solvent such as dichloromethane, toluene, xylene. 
For making an intermediate suitable to make omeprazole, the following process may be carried out: 
The above sequence is preferred; however, step xe2x80x9cdxe2x80x9d could be performed before step xe2x80x9ccxe2x80x9d (Scheme-2). The steps may be carried out in different orders as would be understood by persons skilled in the art. It is preferred to have an electron withdrawing group at the 4-position before functionalizing the 2-position. 
Furthermore, the unreacted starting material in the free radical reaction could easily be recovered by alkaline treatment and extraction with an organic solvent. The 2-alkoxycarbonyl product is obtained in purity higher or equal to 90%. Analytically pure product could be obtained by hydrolysis of the ester to the acid according to methodologies generally known in the art. For example, the hydrolysis of III to the acid (IV) (see Scheme 3) could be accomplished using aqueous sodium hydroxide or aqueous hydrochloric acid. The acid obtained (IV) could then be converted back to the ester using methods generally known in the art. For example, reaction of the acid with thionyl chloride followed by an alcohol such as methanol. On the other hand, the acid could be reduced directly to the alcohol using carboxylic acid reducing agents that are generally known to persons skilled in the art. For example, Diborane, diborane complexes (e.g. Syn. 1979, 704; J. Org. Chem. 1973, 38, 2786), lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, lithium borohydride; these reagents can be used pure or with catalysts and additives (e.g. J. Org. Chem. 1982, 47, 4702; Tet. 1992, 48, 4623). 
While the reaction involving the nucleophilic substitution of the 4-halo substituent generally goes to completion, an ether cleavage product (V) is also usually formed. This product could be recovered from the aqueous layer and treated with an alkylating agent to get the 4-alkoxy product. This 4-nucleophilic substitution reaction can be geared to provide the ether cleavage product, such as (V) and (VI), as the major products. This could be achieved by, for example, employing longer reaction times (over 15 hours). The synthesis of 4-hydroxy products such as compounds (V) and (VI) is also within the scope of this invention. These products are inorganic salts of 4-hydroxypyridines. The 4-hydroxypyridines may also take the form of these organic salts. Compound (V) may be a mono organic/inorganic salt. Compound (VI) may be a mono- or di-organic/inorganic salt (such as the sodium or potassium salt).
The alkylation of the 4-hydroxy compounds could be accomplished employing methods that are generally known to a person skilled in the art. For example, compounds (V) or (VI) could be methylated by treatment with 1 equivalent (for compound V) or 2-5 equivalents (for compound VI) of a methylating agent such as lodomethane, in an inert aprotic solvent such as dimethylformamide. 
According to another aspect of the invention, there is provided a process of reacting a compound of formula II 
wherein
R1=H or CH3 
R2=H or CH3 
R3 is hydrogen
with SOCl2 or any other halogenating agent to form 4-halopyridine derivatives.
In one embodiment the halogenating agent can be used neat, and in another embodiment it can be used in the presence of solvents such as toluene, xylene, chlorobenzene or any other suitable inert solvent. Preferably the reaction occurs substantially solvent free.
The following is a list of the substituents R, R2, R3, R4, R5, on Formula I, that correspond to the substituents on the medicines: